1. Field of the Invention
The invention relates generally to the prostate and specifically to a novel complex of hK2 and PI-6 formed in the prostate, and methods of using the novel complex.
2. Description of the Prior Art
Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citation for these references may be found at the end of this application, preceding the claims.
Three members of the human kallikrein family have been identified so far, designated hK1, hK2 and hK3 (1). All are serine proteases with high sequence identity. Two of these kallikreins, hK2 and hK3, are found almost exclusively in the prostate (extensively reviewed in (2). hK3, known more commonly as prostate-specific antigen, PSA, is a widely used serum marker for prostate. More recently, hK2 has become the focus of investigations into its possible role as a prostate cancer marker, as well as possible roles in prostate cancer biology (2).
hK2 is similar to PSA in many respects such as prostate tissue localization (3; 4), 80% sequence identity (5; 6), and regulation by androgens (7; 8). From a biochemical perspective, hK2 is different from PSA in that it shows a strong trypsin-like activity while PSA has weak chymotrypsin-like activity. However, unlike true kallikreins, hK2 shows little or no kininogenase-like activity (9; 10) and so does not appear to function primarily as a prostatically-expressed kininogenase.
The physiological roles for hK2 have not been established, though several activities have been described. hK2 has been shown to activate the zymogen form of PSA (pPSA) (11-13), and the zymogen of hK2 (autoactivation) (14). In this respect hK2 is unique from the other human tissue kallikreins, hK1 and PSA. The activation of pPSA by hK2 is particularly interesting since it suggests a possible physiological role for hK2 in the regulation of PSA activity.
Immunohistochemical studies using hK2-specific monoclonal antibodies have shown hK2 to be more highly expressed in prostate carcinoma than in normal tissues (15). This is the inverse of PSA which tends to be lower in more poorly differentiated cancer epithelium than in normal tissues.
hK2 has been shown to activate urokinase-type plasminogen activator (uPA) by cleavage of the single-chain uPA at Lys.sup.158 to generate the two-chain active form of uPA (12; 16). It has been recently reported that hK2 rapidly complexes with PAI-1 in vitro and that hK2 also inactivates about 6 moles of PAI-1 during complex formation (17). It is therefore possible that the elevated levels of hK2 in prostate cancer play a biological role either by the activation of urokinase or by the inactivation of PAI-1, the primary inhibitor of urokinase.
Physiologically hK2 has been identified as a complex with ACT in serum (18)and PCI in seminal plasma (19). However, it was not previously known whether hK2 forms any tissue specific complex in the prostate. The physiological and biological role of hK2 in the prostate was also not known. Therefore, a need exists to study the role of hK2 in the prostate, particularly in prostate cancer.